Autografting for Lymphoma

自体造血细胞移植（AHCT）是大多数患者的标准治疗。 常见类型的非霍奇金淋巴瘤，弥漫性大B细胞（DLBCL），复发或主要难治 套细胞淋巴瘤诱导治疗后AHCT的应用 (MCL)已经被证明可以延长疾病的缓解期尽管细胞减灭效果很好，但仍会复发 在MCL和大约一半的DLBCL病例中持续存在。独特的每一个B细胞淋巴瘤是一个 我们在疫苗接种方面所成功追求的具体目标。在目标1中，我们计划接种 独特型脉冲树突状细胞后AHCT在MCL，建立在我们的经验，在开发和使用 这些细胞在移植后（IND #11227），与致敏T细胞一起给药，以 优化有效持久的免疫反应的可能性。我们将测量疫苗接种的效果 通过外周血中肿瘤负荷的分子评估和通过免疫测定， 反应在目标2中，我们将利用FDG-PET功能成像的进步， 标准AHCT后复发率非常高的DLBCL患者的区别。利用现有系统 对于斯坦福大学的中心PET审查，我们将根据以下因素定义极高风险DLBCL患者： 挽救化疗后PET阳性疾病，并根据以下情况计划AHCT后免疫治疗： 遗传随机化在HLA匹配供体的高风险DLBCL患者中（目标2.1），我们将寻求非- 清髓性同种异体HCT采用一种新的预处理方案，包括全淋巴照射 (TLI)抗胸腺细胞球蛋白（ATG）是项目4开发的，在本项目项目1中翻译 格兰特计划我们的经验表明，这种方案保留了移植物抗肿瘤的效果，但 急性移植物抗宿主病（GVHD）的发病率和治疗相关的死亡率降低。对于那些 PET阳性患者无可用供体（目的2.2），我们计划研究尼古丁诱导的杀伤细胞（CIK） 细胞作为AHCT后免疫疗法，建立在我们之前在项目3中使用CIK细胞的经验基础上， 已在本项目中的自体环境中进行了翻译。项目2的统一假设是， 淋巴瘤特异性免疫治疗后应用细胞减少和肿瘤控制建立与 常规AHCT将提高复发风险高的淋巴瘤患者的无事件生存率。我们 目标是开发这种基于免疫的策略，以降低AHCT后疾病复发的风险， 可广泛应用于非霍奇金淋巴瘤患者。项目2与项目1、3、4、6交互， 和8，并得到本计划项目赠款的所有核心的支持。

Autologous hematopoietic cell transplantation (AHCT) is the standard treatment for the most common type of non-Hodgkin's lymphoma, diffuse large B-cell (DLBCL), that recurs or is primarily refractory to induction therapy, and the application of AHCT following induction therapy for mantle cell lymphoma (MCL) has been shown to prolong diseas'e remission. Despite excellent cytoreduction, relapse occurs continuously in MCL and in about half of DLBCL cases. The idiotype unique to each B-cell lymphoma is a specific target that we have successfully pursued for vaccination. In Aim 1, we plan to vaccinate with idiotype-pulsed dendritic cells after AHCT in MCL, building upon our experience in developing and using these cells after transplantation (IND #11227), together with administration of primed T-cells, in order to optimize the likelihood of an effective, durable immune response. We will measure the effects of vaccination by molecular assessment of tumor burden in the peripheral blood and by determination of the immune response. In Aim 2, we will take advantage of advances in functional imaging with FDG-PET that allow the distinction of DLBCL patients with a very high rate of relapse after standard AHCT. Utilizing existing systems for central PET review at Stanford University, we will define very high risk DLBCL patients on the basis of PET-positive disease after salvage chemotherapy and plan post-AHCT immunotherapy on the basis of genetic randomization. In high risk DLBCL patients with HLA matched donors (Aim 2.1), we will pursue non- myeloablative allogeneic HCT utilizing a novel conditioning regimen consisting of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) developed in Project 4 and translated in Project 1 of this Program Project Grant. Our experience with this regimen suggests that graft versus tumor effects are retained but the incidence of acute graft versus host disease (GVHD) and treatment-related mortality is reduced. For those PET-positive patients without an available donor (Aim 2.2), we plan to study cytokine-induced killer (CIK) cells as a post-AHCT immunotherapy, building on our previous experience with CIK cells in Project 3, which has been translated in the autologous setting in this Project. The unifying hypothesis in Project 2 is that lymphoma-specific immunotherapy applied after cytoreduction and tumor control is established with conventional AHCT will improve event-free survival in patients with lymphoma at high risk of recurrence. Our goals are to develop such immune-based strategies to reduce the risk of disease relapse after AHCT that could be broadly applied to non-Hodgkin's lymphoma patients. Project 2 interacts with Projects 1, 3, 4, 6, and 8 and is supported by all of the Cores of this Program Project Grant.